Animal Model Of PTSD Research Articles

PS257. The effects of brain-derived neurotrophic factor (BDNF) micro-infusion on the impaired fear extinction of the animal model of PTSD.

PS257. The effects of brain-derived neurotrophic factor (BDNF) micro-infusion on the impaired fear extinction of the animal model of PTSD.

Influence of daily social stimulation on behavioral and physiological outcomes in an animal model of PTSD.

IntroductionWe have shown in previous work that acute episodes of predator exposure occurring in the context of chronic social instability produced PTSD‐like sequelae in rats. Our animal model of PTSD contained two components: (1) acute trauma, immobilization of rats in close proximity to a cat twice in 10 days, and (2) chronic social instability, 31 days of randomized housing of cage cohorts. Here we tested the hypothesis that daily social stimulation would block the development of the PTSD‐like sequelae.MethodsBeginning 24 h after the first cat exposure, adult male rats were given our established PTSD model, alone or in conjunction with daily social stimulation, in which all rats within a group interacted in a large apparatus for 2 h each day for the final 30 days of the PTSD regimen. All behavioral, for example, anxiety, memory, startle testing, and physiological assessments, for example, body growth, organ weights, and corticosterone levels, took place following completion of the psychosocial stress period.ResultsDaily social stimulation blocked the expression of a subset of PTSD‐like effects, including predator‐based cued fear conditioning, enhanced startle response, heightened anxiety on the elevated plus maze and the stress‐induced suppression of growth rate. We also found that social stimulation and psychosocial stress produced equivalent outcomes in some measures, including adrenal and heart hypertrophy, thymus atrophy, and a reduction in poststress corticosterone levels.ConclusionsDaily exposure of rats to a highly social environment blocked the development of a subset of trauma‐induced sequelae, particularly fear‐related outcomes. It is notable that daily social stimulation normalized a subset, but not all, of the PTSD‐like effects. We discuss our findings in the context of the literature demonstrating that social stimulation can counteract the adverse effects of traumatic stress on behavioral and physiological measures, as well as to produce its own stress‐like outcomes.

Predator-scent stress, ethanol consumption and the opioid system in an animal model of PTSD

Emerging literature points to stress exposure as a potential contributor to the development of alcohol abuse, but animal models have yielded inconsistent results. Converging experimental data indicate that the endogenous opioid system modulates alcohol consumption and stress regulation. The aim of the present study is to examine the interplay between stress exposure, behavioral stress responses, ethanol (EtOH) consumption and the endogenous opioid system in an animal model of posttraumatic stress disorder. Rats were exposed to stress and then tested in a two-bottle free choice (TBC) assay or in a conditioned place preference paradigm. In some experiments, the endogenous opioid system was pharmacologically manipulated prior to stress exposure. The behavioral outcomes of stress exposure were assessed in an elevated plus-maze, with the acoustic startle response, and by monitoring the freezing response to trauma reminder. Immunoreactivity of phosphorylated opioid receptors in hippocampal subregions was also measured. Stress significantly increased the consumption of EtOH in the TBC assay. The severity of the behavioral response to stress was associated with EtOH consumption, cue-triggered freezing response to a trauma reminder, and endogenous levels of phosphorylated opioid receptors in the hippocampus. Pharmacologically manipulating the endogenous opioid system prior to stress exposure attenuated trauma cue-triggered freezing responses and blocked predator scent stress-induced potentiation of EtOH consumption. These data demonstrate a stress-induced potentiation of EtOH self-administration and reveal a clear association between individual patterns of the behavioral response to stress and alcohol preference, while indicating a role for the endogenous opioid system in the neurobiological response to stress.

Exercise Enhances the Behavioral Responses to Acute Stress in an Animal Model of PTSD.

This study examined the effects of endurance exercise on the behavioral response to stress and patterns of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), and δ-opioid receptor (phospho-DOR) expression in the hippocampus. Animals ran on a treadmill at 15 m·min, 5 min·d gradually increasing to 20 min·d, 5 d·wk for 6 wk. After training, one group of animals was exposed to a predator scent stress (PSS) protocol for 10 min. Outcome measurements included behavior in an elevated plus-maze (EPM) and acoustic startle response (ASR) 7 d after exposure to stress. Immunohistochemical technique was used to detect the expression of the BDNF, NPY, and phospho-DOR in the hippocampus 8 d after exposure. Sedentary animals exposed to PSS were observed to have a greater incidence of extreme behavior responses including higher anxiety, less total activity in the EPM, and greater amplitude in the ASR than unexposed and/or trained animals. Exercise-trained animals exposed to PSS developed a resiliency to the stress, reflected by significantly greater total activity in the EPM, reduced anxiety, and reduced ASR compared to the sedentary, exposed animals. Exercise in the absence of stress significantly elevated the expression of BDNF and phospho-DOR, whereas exposure to PSS resulted in a significant decline in the expression of NPY, BDNF, and phospho-DOR. Trained animals that were exposed maintained expression of BDNF, NPY, and phospho-DOR in most subregions of the hippocampus. Results indicated that endurance training provided a mechanism to promote resilience and/or recovery from stress. In addition, exercise increased expression of BDNF, NPY, and DOR signaling in the hippocampus that was associated with the greater resiliency seen in the trained animals.

Psychosocial predator-based animal model of PTSD produces physiological and behavioral sequelae and a traumatic memory four months following stress onset

We have a well-established animal model of PTSD composed of predator exposure administered in conjunction with social instability that produces PTSD-like behavioral and physiological abnormalities one month after stress initiation. Here, we assessed whether the PTSD-like effects would persist for at least 4months after the initiation of the psychosocial stress regimen. Adult male Sprague–Dawley rats were exposed to either 2 or 3 predator-based fear conditioning sessions. During each session, rats were placed in a chamber for a 3-min period that terminated with a 30-s tone, followed by 1h of immobilization of the rats during cat exposure (Day 1). All rats in the stress groups received a second fear conditioning session 10days later (Day 11). Half of the stress rats received a third fear conditioning session 3weeks later (Day 32). The two cat-exposed groups were also exposed to daily unstable housing conditions for the entire duration of the psychosocial stress regimen. The control group received stable (conventional) housing conditions and an equivalent amount of chamber exposure on Days 1, 11 and 32, without cat exposure. Behavioral testing commenced for all groups on Day 116. The stress groups demonstrated increased anxiety on the elevated plus maze, impaired object recognition memory and robust contextual and cued fear conditioned memory 3months after the last conditioning session. Combined data from the two stress groups revealed lower post-stress corticosterone levels and greater diastolic blood pressure relative to the control group. These findings indicate that predator-based psychosocial stress produces persistent PTSD-like physiological and behavioral abnormalities that may provide insight into the neurobiological and endocrine sequelae in traumatized people with PTSD.

Effects of Intranasal Neuropeptide Y and HS014 in Preventing Anxiety and Depressive‐like Behavior Elicited by Single Prolonged Stress Animal Model of PTSD: Comparative Study

Stress triggered neuropsychiatric disorders are a serious societal problem. Prophylactic treatment or early intervention has great potential in increasing resilience to traumatic stress and reducing its harmful impact. Previously, we demonstrated proof of concept that intranasal administration of NPY or the MC4 receptor antagonist, HS014, prior to single prolonged stress (SPS) rodent PTSD model, can prevent or attenuate many PTSD associated impairments. Here, we compare effects of NPY and HS014 given 30 min before or immediately after SPS stressors on development of anxiety, depressive‐like behavior and associated biochemical abnormalities. SPS triggered anxiety on EPM was reduced by intranasal pre‐administration of 100 µg NPY and to even greater extent HS014 (3.5 ng or 100 µg). The SPS‐elicited depressive‐like behavior on FST was prevented with 100 µg NPY or the high dose HS014. Combined administration of low HS014 and NPY, ineffective by themselves, prevented development of depressive‐like behavior. Reductions in stress triggered activation of LC/noradrenergic system and HPA axis were observed with both HS014 and NPY. In contrast to NPY, early intervention with HS014 immediately after SPS did not prevent the development of anxiogenic behavior on EPM. However, HS014 given after SPS stressors, even at very low dose, prevented development of depressive‐like behavior. Thus, both MC4R antagonist and NPY, alone or combined, have potential for prophylactic treatment against traumatic stress triggered anxiety or depressive‐like behaviors, while NPY has more widespread potential for early intervention. (Supported by US Amy grant DM102281)

Beyond the HPA-axis: The role of the gonadal steroid hormone receptors in modulating stress-related responses in an animal model of PTSD

The hypothalamic–pituitary–adrenal (HPA) axis, which plays a major role in the response to stress, and the hypothalamic–pituitary–gonadal (HPG) axis are closely linked with the ability to inhibit the other. Testosterone, a product of the HPG, has many beneficial effects beyond its functions as a sex hormone including anti-anxiety properties. In this study we examined the effect of stress exposure on gonadal hormones, and their efficacy in modulating anxiety-like response in an animal model of PTSD. Male rats were exposed to predator scent stress, followed by analysis of brain expression of androgen receptor (AR) receptor and estrogen receptor α (ERα). The behavioral effects of immediate treatment with testosterone, testosterone receptor antagonist (flutamide) or vehicle were evaluated using the elevated plus-maze, acoustic startle response and trauma-cue response. Levels of circulating corticosterone and testosterone were also measured after treatment. The behavioral effects of delayed testosterone treatment were explored in the same manner. We report that animals whose behavior was extremely disrupted (EBR) selectively displayed significant down-regulation of AR and ERα in the hippocampus. Immediate treatment with flutamide or delayed treatment with testosterone significantly increased prevalence rates of minimal behavioral response (MBR) and decreased prevalence of EBR with favorable behavioral results. Testosterone levels were higher in control un-exposed animals, while corticosterone was higher in control exposed animals. This study suggests that gonadal steroid hormones are involved in the neurobiological response to predator scent stress and thus warrant further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.

Distinctive hippocampal and amygdalar cytoarchitectural changes underlie specific patterns of behavioral disruption following stress exposure in an animal model of PTSD

Alterations in cytoarchitecture and molecular signaling have been observed in adaptive and maladaptive responses to stress and presumably underlie the physiological and behavioral changes observed. The relationship between behavioral responses to stress exposure and changes in cytoarchitecture of subregions of the hippocampus and amygdala was investigated in an animal model of PTSD.Behaviors in elevated plus-maze and acoustic startle response tests were assessed in rats 7 days after exposure to predator scent stress. Brains were harvested 24h later. Neurons from CA1, CA3, and dentate gyrus subregions and basolateral amygdala were reconstructed and subjected to Sholl analysis and spine density estimation. Glucocorticoid receptor, brain-derived neurotrophic factor, phospho-NR1-Ser-889, phospho-GluR1-Ser-845, phospho-calcium/calmodulin dependent protein kinase II-Thy-286, post-synaptic density protein 95 and phospho-CREB-Ser-133 were evaluated in the hippocampus. Data were analyzed by retrospective classification of individual rats into three behavioral response groups.The extent and distribution of changes in the morphology of hippocampal and amygdalar dendrites was significantly associated with stress-induced behavioral response classification. Extreme (PTSD-like) behavioral disruption was associated with extensive neuronal retraction in the hippocampus and proliferation in the amygdala. Neither structure displayed such changes in minimal behavioral responders. Partial behavioral response was associated with identical changes in the hippocampus only. Patterns of change in requisite molecular signaling genes and endophenotypic markers corresponded to the structural and behavioral responses. The extent and distribution of changes in the cytoarchitecture of hippocampal and amygdalar subregions is directly related to the pattern of behavioral response of the individual to stress exposure.

How Traumatic Experiences Leave Their Signature on the Genome: An Overview of Epigenetic Pathways in PTSD.

How Traumatic Experiences Leave Their Signature on the Genome: An Overview of Epigenetic Pathways in PTSD.

Expression of amygdala mineralocorticoid receptor and glucocorticoid receptor in the single-prolonged stress rats.

BackgroundPost-traumatic stress disorder (PTSD) is an anxious disorder associated with low levels of corticosterone and enhanced negative feedback of the hypothalamic–pituitary–adrenal (HPA) axis. Previous studies showed that the amygdala not only has an excitatory effect on the HPA axis but also plays a key role in fear-related behaviors. Coticosterone exert actions through binding to the mineralocorticoid (MR) and glucocorticoid receptor (GR), which are abundant in the amygdala. In our previous study, down-regulation of MR and GR in the hippocampus of PTSD rats was found. But the roles of MR and GR in the amygdala of PTSD rats is incompletely understood.Resultswistar rats were divided into 1 d, 7 d, 14 d groups after single prolonged stress (SPS) and control group. SPS is a reliable animal model of PTSD. Open field test (OF) and elevated plus maze tests (EPM) were performed to examine fear-related behaviors. Morphological changes of the ultrastructure of the amygdala neurons were assessed by transmission electron microscopy (TEM). Dual-immunofluorescence histochemistry was used to determined subcellular distribution and colocalization of MR- and GR-ir. Protein and mRNA of MR and GR was examined by western blotting and RT-PCR. OF and EPM showed enhanced fear in SPS rats. Abnormal neuronal morphology was discovered in the amygdala of SPS rats. The expression of MR- and GR-ir intensity, mRNA and protein within the amygdala decreased after SPS at 1 day, and then gradually recovered by 14 days, although the degree of decrease and recovery were different amongst techniques. We found no change in the MR/GR ratio at 3 levels of the amygdala. But more cytoplasmic distribution and decreased colocalization of MR- and GR-ir were observed in the amygdala after 7 days of SPS.ConclusionThese data suggest that change of MR and GR in the amygdala are involved in the mechanisms of fear in PTSD.

Effects of Chronic Psychosocial Stress on Reduction of Basal Glucocorticoid Levels and Suppression of Glucocorticoid Levels Following Dexamethasone Administration in Animal Model of PTSD

Aim: To further examine the neurobiological mechanisms and their outcomes responsible for the PTSD sequelae induced by laboratory animal model and to explore the effects of chronic psychosocial paradigm. We tested the hypothesis that our animal model of PTSD would display abnormalities in glucocorticoid levels that are manifest in people with PTSD and that psychosocially stressed rats exhibit a significantly greater suppression of corticosterone levels than control rats following the administration of dexamethasone.Methods: Animals were divided into two groups. The experimental group was scheduled to exposure to two types of stressors: double exposure to acute immobilization stress, and combined predator-threat stress and daily social stress. There was also administration of dexamethasone in combination with stress exposure.Results: There was a statistical difference between masses of thymus in the stress group and stress group with dexamethasone appliance (p=0.024). We found statistical significance between baseline cortisol and stress induced levels of cortisol and between stress induced group and return to baseline group.Conclusion: Significant changes in HPA activity, reductions in basal glucocorticoid levels and enhanced dexamethasone induced inhibition of glucocorticoid levels have been manifested. All of this is manifested in PTSD patients also as many other stress induces changes.

Effects of Chronic Psychosocial Stress on Reduction of Basal Glucocorticoid Levels and Suppression of Glucocorticoid Levels Following Dexamethasone Administration in Animal Model of PTSD

Aim: To further examine the neurobiological mechanisms and their outcomes responsible for the PTSD sequelae induced by laboratory animal model and to explore the effects of chronic psychosocial paradigm. We tested the hypothesis that our animal model of PTSD would display abnormalities in glucocorticoid levels that are manifest in people with PTSD and that psychosocially stressed rats exhibit a significantly greater suppression of corticosterone levels than control rats following the administration of dexamethasone.Methods: Animals were divided into two groups. The experimental group was scheduled to exposure to two types of stressors: double exposure to acute immobilization stress, and combined predator-threat stress and daily social stress. There was also administration of dexamethasone in combination with stress exposure.Results: There was a statistical difference between masses of thymus in the stress group and stress group with dexamethasone appliance (p=0.024). We found statistical significance between baseline cortisol and stress induced levels of cortisol and between stress induced group and return to baseline group.Conclusion: Significant changes in HPA activity, reductions in basal glucocorticoid levels and enhanced dexamethasone induced inhibition of glucocorticoid levels have been manifested. All of this is manifested in PTSD patients also as many other stress induces changes.

The basolateral amygdala determines the effects of fear memory on sleep in an animal model of PTSD

Fear conditioning [inescapable shock training (ST)] and fearful context re-exposure (CR) alone can produce significant fear indicated by increased freezing and reductions in subsequent rapid eye movement (REM) sleep. Damage to or inactivation of the basolateral nucleus of the amygdala (BLA) prior to or after ST or prior to CR generally has been found to attenuate freezing in the shock training context. However, no one has examined the impact of BLA inactivation on fear-induced changes in sleep. Here, we used the GABAA agonist, muscimol (MUS), to inactivate BLA prior to ST, the period when fear is learned, and assessed sleep after ST and sleep and freezing after two CR sessions. Wistar rats (n = 14) were implanted with electrodes for recording sleep and with cannulae aimed bilaterally into BLA. After recovery, the animals were habituated to the injection procedure (handling) over 2 consecutive days and baseline sleep following handling was recorded. On experimental day 1, the rats were injected (0.5 μl) into BLA with either MUS (1.0 μM; n = 7) or vehicle (distilled water, n = 7) 30 min prior to ST (20 footshocks, 0.8 mA, 0.5-s duration, 60-s interstimulus interval). On experimental days 7 and 21, the animals experienced CR (CR1 and CR2, respectively) alone. Electroencephalogram and electromyogram were recorded for 8 h on each day, and the recording was scored for non-rapid eye movement sleep, REM sleep, and wakefulness. Freezing was examined during CR1 and CR2. MUS microinjections into BLA prior to ST blocked the post-training reduction in REM sleep seen in vehicle-treated rats. Furthermore, in MUS-treated rats, REM sleep after CR1 and CR2 was at baseline levels and freezing was significantly attenuated. Thus, BLA inactivation prior to ST blocks the effects of footshock stress on sleep and reduces fear memory, as indicated by the lack of freezing and changes in sleep after CR. These data indicate that BLA is an important regulator of stress-induced alterations in sleep and an important site for forming fear memories that can alter sleep.

Intranasal neuropeptide Y reverses anxiety and depressive-like behavior impaired by single prolonged stress PTSD model

PTSD is a debilitating neuropsychiatric disorder and many patients do not respond sufficiently to current treatments. Neuropeptide Y (NPY) is suggested to provide resilience to the development of PTSD and co-morbid depression. Injections of NPY to the rodent brain are anxiolytic. Recently we showed that intranasal delivery of NPY to rats before or immediately after exposure to single prolonged stress (SPS) animal model of PTSD prevented development of many biochemical and behavioral symptoms of PTSD, indicating its prophylactic potential. Here, we investigated whether intranasal NPY might provide benefits once symptoms have already developed. One week after exposure to SPS stressors, animals were given intranasal NPY or vehicle and tested on elevated plus maze 2h or 2 days later. The NPY treated rats had lower anxiety-like behavior than vehicle treated rats as indicated by more entries into open arms and fewer into closed arms, lower anxiety index, higher risk assessment and unprotected head dips and reduced grooming time. Their anxiety index was similar to that of unstressed controls. On most of these variables there was no effect of time interval and rats displayed similar overall changes 2h or 2 days after the infusion. Moreover, intranasal NPY led to reduced depressive-like behavior, assessed by forced swim test. Thus, intranasal NPY reversed several behavioral impairments triggered by the traumatic stress of SPS and has potential for non-invasive PTSD therapeutic intervention.

Neuropeptide Y (NPY) infusion attenuates development of PTSD‐like symptoms to traumatic stress in rats

NPY has anxiolytic properties associated with resilience to stress‐related disorders, such as PTSD. However, due to its hypertensive effects, peripheral administration is undesirable, thus we used intranasal (IN) infusion. Rats were pretreated with single IN NPY or vehicle before exposure to single prolonged stress (SPS) animal model of PTSD and compared to untreated controls. Thirty min after SPS the elevation of plasma ACTH and corticosterone was not as pronounced in NPY‐infused rats and the induction of tyrosine hydroxylase (TH) in locus coeruleus (LC) was attenuated. Seven days after SPS, they displayed reduction in development of anxiety, depressive‐like behavior and hyperarousal. Plasma ACTH, corticosterone, and hippocampal glucocorticoid receptor levels were significantly above controls only in the vehicle, but not IN NPY‐treated. Baseline TH mRNA levels in LC did not differ among groups, but increased with forced swim in the vehicle‐, but not NPY‐pretreated animals. Administration of IN NPY immediately post‐SPS led to a similar reduction in PTSD associated behaviors. The results show that IN NPY can alter stress‐triggered dysregulation of the HPA axis and activation of central noradrenergic activity and provide proof of concept for potential of IN NPY as a non‐invasive prophylactic treatment or early intervention in response to traumatic stress. Supported by US army grant DM102881.

Systemic administrations of β-estradiol alleviate both conditioned and sensitized fear responses in an ovariectomized rat model of post-traumatic stress disorder

Although no single widely accepted animal model of PTSD has been established to date, the single prolonged stress (SPS) animal model has been partially validated as a model for PTSD. SPS rats mimic the pathophysiological abnormalities and behavioral characteristics of PTSD, such as enhanced fear response to the traumatic cue (conditioned fear response) and hyper arousal (the sensitized fear response). In the present study we are looking at PTSD-like symptoms in rats. We examined whether Systemic administrations of β-estradiol could alleviate PTSD-like symptoms that are induced by SPS model.In this study, electric foot shocks (two 4s, 1mA with an interval of 30s) were given to Adult ovariectomized rats 1day after SPS procedures. Additionally, β-estradiol (45, 90, and 180μg/kg) or sesame oil (vehicle) were injected immediately after foot shock and before Tests 2 and 3. After different incubation times, one (Test 1), two (Test 2), and three (Test 3) weeks later, the conditioned or sensitized fear responses were measured (Percent of freezing during test) by re-exposing the stressed rats to the shock chamber or a neutral tone in a novel environment. Three other groups were shock, control and sham groups. Ovariectomized rats of Shock group received shocks conducted through the procedure described below on. Animals in control (Ovariectomized rats) and Sham groups (Only submitted to surgery without removal of the ovaries), neither were exposed to the SPS procedure nor received an electrical shock. Also, these three groups were tested for fear responses three times.Findings indicated that rats who received electric shock the day after SPS exhibited both enhanced conditioned and sensitized fear responses in comparison to the control group. β-estradiol in 45μg/kg dose could reduce both types of fear responses. β-estradiol exert an inhibitory influence on contextual fear conditioning (hippocampal-dependent) and on sensitized fear conditioning (amygdala-dependent). Single injection of this dose is enough for CFR alleviation but at least twice injections are necessary to reduce sensitized fear response. Overall our data demonstrate that multiple injections of β-estradiol, dose dependently, could alleviate both SPS induced conditioned and sensitized fear responses, as signs of PTSD.

Beyond the HPA-axis: the role of the gonadal steroid hormone receptors in modulating stress related responses in an animal model of PTSD

Beyond the HPA-axis: the role of the gonadal steroid hormone receptors in modulating stress related responses in an animal model of PTSD

High dose corticosterone immediately after stress exposure prevents hippocampal cytoarchitecture and neuronal plasticity damage in an animal model of PTSD

High dose corticosterone immediately after stress exposure prevents hippocampal cytoarchitecture and neuronal plasticity damage in an animal model of PTSD

Animal model of PTSD based on clinically relevant features of trauma susceptibility and expression

Animal model of PTSD based on clinically relevant features of trauma susceptibility and expression

The Neuropeptide Y (NPY)-ergic System is Associated with Behavioral Resilience to Stress Exposure in an Animal Model of Post-Traumatic Stress Disorder

Converging evidence implicates the regulatory neuropeptide Y (NPY) in anxiety- and depression-related behaviors. The present study sought to assess whether there is an association between the magnitude of behavioral responses to stress and patterns of NPY in selected brain areas, and subsequently, whether pharmacological manipulations of NPY levels affect behavior in an animal model of PTSD. Animals were exposed to predator-scent stress for 15 min. Behaviors were assessed with the elevated plus maze and acoustic startle response tests 7 days later. Preset cutoff criteria classified exposed animals according to their individual behavioral responses. NPY protein levels were assessed in specific brain regions 8 days after the exposure. The behavioral effects of NPY agonist, NPY-Y1-receptor antagonist, or placebo administered centrally 1 h post-exposure were evaluated in the same manner. Immunohistochemical technique was used to detect the expression of the NPY, NPY-Y1 receptor, brain-derived neurotrophic factor, and GR 1 day after the behavioral tests. Animals whose behavior was extremely disrupted (EBR) selectively displayed significant downregulation of NPY in the hippocampus, periaqueductal gray, and amygdala, compared with animals whose behavior was minimally (MBR) or partially (PBR) disrupted, and with unexposed controls. One-hour post-exposure treatment with NPY significantly reduced prevalence rates of EBR and reduced trauma-cue freezing responses, compared with vehicle controls. The distinctive pattern of NPY downregulation that correlated with EBR as well as the resounding behavioral effects of pharmacological manipulation of NPY indicates an intimate association between NPY and behavioral responses to stress, and potentially between molecular and psychopathological processes, which underlie the observed changes in behavior. The protective qualities attributed to NPY are supported by the extreme reduction of its expression in animals severely affected by the stressor and imply a role in promoting resilience and/or recovery.